Rodents reared in enriched conditions (EC) during childhood and adolescence have a variety of neurobiological and behavioral differences when compared to rodents reared in standard (SC) or isolated conditions (IC). These neurobiological differences impact numerous behaviors, including the response to a variety of drugs of abuse. It is well established that rearing in an EC reduces the motivation to respond for low doses of psychostimulants when compared to rats raised in an IC, however, the neurobiological mechanism for this effect remains unclear. Several studies have observed differences in dopaminergic function in the mesocorticolimbic pathway between EC and IC rats. Glutamatergic afferents to the mesocorticolimbic pathway mediate the response to psychostimulants and deficits in glutamate homeostasis are hypothesized to contribute to drug addiction. Differential rearing alters glutamatergic function and therefore the overarching hypothesis of the current application is that differential rearing alters glutamate homeostasis. It is predicted that enrichment augments glutamate homeostasis and this augmentation contributes to the ability of enrichment to protect against drug abuse. Conversely, isolation impairs glutamate homeostasis and this impairment contributes to the increased vulnerability to drug abuse. Specific Aim 1 will determine if differential rearing alters the function of receptors and transporters critical for glutamate homeostasis. The effect of agonists and antagonists to mGluR2/3, mGluR5, and GLT1on the self-administration of amphetamine in differentially reared rats will be examined. Specific Aim 2 will examine if differential rearing alters the expression of proteins that contribue to the maintenance of glutamate homeostasis. The expression of mGluR2/3, mGluR5, and GLT1 in the mesocorticolimbic dopamine pathway will be measured following acute and repeated amphetamine in differentially reared rats. Results supporting this hypothesis will suggest that environmental conditions alter glutamatergic function and that these changes affect drug use behavior. Use of the differential rearing model in the current application will enable future testing of the glutamate homeostasis theory in a model that displays an environmentally-induced continuum of reward sensitivity to validate, expand, and apply the glutamate homeostasis theory. These experiments will be conducted by undergraduate and graduate students. Completion of the proposed experiments will strengthen the research environment in the Kansas State University Psychology Department and will enable students to participate in all phases of a research program exploring the effects of differential rearing on glutamate homeostasis.